Long-term weight management by dieting has a high failure rate. Pharmacological targets have focused on appetite reduction, although less is understood as to the potential contributions of the stress state during dieting in long-term behavioral modification. In a mouse model of moderate caloric restriction in which a 10-15% weight loss similar to human dieting is produced, we examined physiological and behavioral stress measures. After 3 weeks of restriction, mice showed significant increases in immobile time in a tail suspension test and stress-induced corticosterone levels. Increased stress was associated with brain region-specific alterations of corticotropin-releasing factor expression and promoter methylation, changes that were not normalized with refeeding. Similar outcomes were produced by high-fat diet withdrawal, an additional component of human dieting. In examination of long-term behavioral consequences, previously restricted mice showed a significant increase in binge eating of a palatable high-fat food during stress exposure. Orexigenic hormones, melanin-concentrating hormone (MCH) and orexin, were significantly elevated in response to the high-fat diet only in previously restricted mice. Furthermore, administration of the MCH receptor-1 antagonist GSK-856464 [4-(4-ethyl-5-methylsulfanyl-1,2,4-triazol-3-yl)pyridine] significantly reduced total caloric intake in these mice during high-fat access. These results reveal reprogramming of key central pathways involved in regulating stress responsivity and orexigenic drives by moderate caloric restriction experience. In humans, such changes would be expected to reduce treatment success by promoting behaviors resulting in weight regain, and suggest that management of stress during dieting may be beneficial in long-term maintenance.